European Heart Journal – Cardiovascular Imaging (2015) 16, 154–155 doi:10.1093/ehjci/jeu275
EDITORIAL
‘Black box warning’ on food and drug administration criteria for drug-induced heart valve disease? Bernard Cosyns 1,2* and Steven Droogmans 2 1
Department of Cardiology, UZ VUB, 101 Laarbeeklaan, Brussels 1090, Belgium; and 2CHVZ, UZ Brussel, Brussels, Belgium
Online publish-ahead-of-print 22 December 2014
common and are often associated with some degree of AR or MR. Therefore, the following score6 has been proposed based on an integrative approach recommended by the European Association of Cardiovascular Imaging.7 (Score from 1 to 4: from very likely to unlikely): (1) Proved restrictive VHD (confirmed with histopathology and/ or regression after interruption of ergot treatment); (2) Important restrictive valve disease (regurgitation .2/4) or restrictive tricuspid disease even if regurgitation ,2/4; (3) Mild to moderate (regurgitation ,2/4) restrictive valve disease; (4) No restrictive valve dysfunction. Moreover, an even more integrative approach encompassing both clinical and echocardiographic parameters is required in the assessment of DIHVD. Indeed, some factors like hypertension have been shown to increase susceptibility to DIHVD even with low dose of these drugs.4 On the other hand, blood pressure remains an important parameter to adequately assess valve disease in general. Use of low-dose cabergoline in hyperprolactinomas is still a matter of concern regarding its potential role in DIHVD. Although recent studies are reassuring, an integrative approach to assess valve disease still needs to be set up.8 This is of major importance since new anorectic drugs have been recently released and even approved in the USA like lorcaserin. Lorcaserin is a selective 5-HT2c agonist evaluated for weight management in clinical trials. But still, locarserin has a 5-HT2B effect, and a report of the FDA in September 2010 has emphasized the presence of a 10-fold variation of the estimated potency of locarserin for the 5HT receptors across in vitro studies. Receptor selectivity of lorcaserin in different tissues in vivo is difficult to predict due to variable in vitro potency data. Although there was no evidence that lorcaserin induced fibrotic lesions of cardiac tissue in animals up to 100 times the clinical Cmax and 70 times clinical AUC, toxicology studies did not include a ‘positive control’ for DIHVD. Moreover, other drug-
The opinions expressed in this article are not necessarily those of the Editors of EHJCI, the European Heart Rhythm Association or the European Society of Cardiology.
* Corresponding author. Tel: +32 23890440; Fax: +32 23873065, E-mail: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
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In the study by Marechaux et al., the authors performed a prospective multi-centre observational and cross-sectional study evaluating the presence of mitral- and/or aortic valve disease in a large number of patients exposed to valvulopathic drugs (mainly benfluorex) compared with a control group of diabetics not exposed. For the diagnosis of drug-induced valvular heart disease (DIVHD), they used an integrative approach combining both colour Doppler and valvular morphological characteristics as a ‘gold standard’ in contrast to the classical Food and Drug Administration (FDA) criteria used in other studies with fenfluramine, MDMA (Ecstasy), pergolide, and cabergoline. They conclude that FDA criteria solely based on Doppler detection underestimate the frequency of mitral valve and overestimate aortic DIVHD.1 Although most of these toxic drugs (including benfluorex) have subsequently been withdrawn from the market, several cases of patients requiring valve surgery late after the cessation of therapy have been reported, emphasizing the long-term implications of DIVHD.2,3 Moreover, the exact incidence of patients presenting DIHVD is difficult to establish. The clinical presentation is variable, and some patients were taking multiple anorectic drugs. Reporting of echocardiographically detected DIVHD was highest in the USA when funding became available after several damage claims and has dramatically decreased after reimbursement was suppressed. In the particular case of benfluorex, the number of out of label prescriptions in obese patients without diabetes is not precisely known, making the definition of an appropriate control group even more difficult. Although for benfluorex, the relationship with the development of DHIVD is clearly established, the causality is less well demonstrated than for other drugs.4 The presence of trivial to moderate aortic regurgitation (AR) or moderate-to-severe mitral regurgitation (MR) was the criterion proposed by the FDA to confirm fenfluramine-induced valvulopathy in the late nineties. 5 In younger patients under the age of 50 years with a low background prevalence of AR and MR, such abnormalities can be easily identified. Conversely, in older patients with Parkinson’s disease, pre-existing valvular sclerosis and calcifications are relatively
155
Editorial
References 1. Mare´chaux S, Rusinaru D, Jobic Y, Ederhy S, Donal E, Reant P et al. Food and Drug Administration criteria for the diagnosis of drug-induced valvular heart disease in patients previously exposed to benfluorex: a prospective multicenter study. Eur Heart J Cardiovasc Imaging 2015;16:158 –65. 2. Dahl CF, Allen MR, Urie PM, Hopkins PN. Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals. BMC Med 2008;6:34. 3. Greffe G, Chalabreysse L, Mouly-Bertin C, Lantelme P, Thivolet F, Aulagner G et al. Valvular heart disease associated with fenfluramine detected 7 years after discontinuation of treatment. Ann Thorac Surg 2007;83:1541 –3. 4. Droogmans S, Cosyns B, Van Camp G. Pergolide and valvular heart disease: the lower the better? Eur J Echocardiogr 2008;9:717 –8. 5. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services interim public health recommendations, November 1997. MMWR Morb Mortal Wkly Rep 1997;46:1061 – 6. 6. Cosyns B, Droogmans S, Rosenhek R, Lancellotti P. Drug-induced valvular heart disease. Heart 2013;99:7 –12. 7. Lancellotti P, Tribouilloy C, Hagendorff A, Popescu BA, Edvardsen T, Pierard LA et al. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging. Scientific Document Committee of the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2013;14:611 –44. 8. Drake WM, Stiles CE, Howlett TA, Toogood AA, Bevan JS, Steeds RP et al. A cross-sectional study of the prevalence of cardiac valvular abnormalities in hyperprolactinemic patients treated with ergot-derived dopamine agonists. J Clin Endocrinol Metab 2014;99:90 –6. 9. Weissman NJ, Sanchez M, Koch GG, Smith SR, Shanahan WR, Anderson CM. Echocardiographic assessment of cardiac valvular regurgitation with lorcaserin from analysis of 3 phase 3 clinical trials. Circ Cardiovasc imaging 2013;6:560–7. 10. Lorcaserin. In obesity: unacceptable risks. Prescrire Int 2014;23:117–20.
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induced VHD-related endpoints reported in the literature were not included in the preclinical evaluation for lorcaserin (proliferative markers, echocardiography). A recent publication by Weissman and colleagues9 compiling the echocardiographic follow-up of 5249 patients of three-phase, three clinical trials exposed to lorcarserin concluded that the rate of echocardiographic valvulopathy was similar to placebo. In this study, the FDA criteria for DIHVD and the change in regurgitation grade were used for analysis of the data. Following the results of Marechaux et al., this may lead to misinterpretation of the data and false reassurance regarding the use of this drug, as already pointed by others.10 To summarize, regarding drug-induced valve disease, the method used to characterize the type and severity of the valvular lesion that is screened for changes in the sensitivity and specificity of disease detection. Moreover, the objective definition of the epidemiology of DIVHD is dependent on a number of factors: the performance and/or interpretation of the echocardiogram in a non-blinded fashion and other potential co-determinants including pre-existent VHD, age, obesity, diabetes and hypertension. By consequence, great vigilance is still required. On one hand, the late effect of valvulopathic drugs may lead to valve disease even a long time after withdrawn from the market or cessation of these drugs. On the other hand, new drugs released on the market may cause more harm than initially expected.
EDITORIAL
‘Black box warning’ on food and drug administration criteria for drug-induced heart valve disease? Bernard Cosyns 1,2* and Steven Droogmans 2 1
Department of Cardiology, UZ VUB, 101 Laarbeeklaan, Brussels 1090, Belgium; and 2CHVZ, UZ Brussel, Brussels, Belgium
Online publish-ahead-of-print 22 December 2014
common and are often associated with some degree of AR or MR. Therefore, the following score6 has been proposed based on an integrative approach recommended by the European Association of Cardiovascular Imaging.7 (Score from 1 to 4: from very likely to unlikely): (1) Proved restrictive VHD (confirmed with histopathology and/ or regression after interruption of ergot treatment); (2) Important restrictive valve disease (regurgitation .2/4) or restrictive tricuspid disease even if regurgitation ,2/4; (3) Mild to moderate (regurgitation ,2/4) restrictive valve disease; (4) No restrictive valve dysfunction. Moreover, an even more integrative approach encompassing both clinical and echocardiographic parameters is required in the assessment of DIHVD. Indeed, some factors like hypertension have been shown to increase susceptibility to DIHVD even with low dose of these drugs.4 On the other hand, blood pressure remains an important parameter to adequately assess valve disease in general. Use of low-dose cabergoline in hyperprolactinomas is still a matter of concern regarding its potential role in DIHVD. Although recent studies are reassuring, an integrative approach to assess valve disease still needs to be set up.8 This is of major importance since new anorectic drugs have been recently released and even approved in the USA like lorcaserin. Lorcaserin is a selective 5-HT2c agonist evaluated for weight management in clinical trials. But still, locarserin has a 5-HT2B effect, and a report of the FDA in September 2010 has emphasized the presence of a 10-fold variation of the estimated potency of locarserin for the 5HT receptors across in vitro studies. Receptor selectivity of lorcaserin in different tissues in vivo is difficult to predict due to variable in vitro potency data. Although there was no evidence that lorcaserin induced fibrotic lesions of cardiac tissue in animals up to 100 times the clinical Cmax and 70 times clinical AUC, toxicology studies did not include a ‘positive control’ for DIHVD. Moreover, other drug-
The opinions expressed in this article are not necessarily those of the Editors of EHJCI, the European Heart Rhythm Association or the European Society of Cardiology.
* Corresponding author. Tel: +32 23890440; Fax: +32 23873065, E-mail: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
Downloaded from by guest on November 13, 2015
In the study by Marechaux et al., the authors performed a prospective multi-centre observational and cross-sectional study evaluating the presence of mitral- and/or aortic valve disease in a large number of patients exposed to valvulopathic drugs (mainly benfluorex) compared with a control group of diabetics not exposed. For the diagnosis of drug-induced valvular heart disease (DIVHD), they used an integrative approach combining both colour Doppler and valvular morphological characteristics as a ‘gold standard’ in contrast to the classical Food and Drug Administration (FDA) criteria used in other studies with fenfluramine, MDMA (Ecstasy), pergolide, and cabergoline. They conclude that FDA criteria solely based on Doppler detection underestimate the frequency of mitral valve and overestimate aortic DIVHD.1 Although most of these toxic drugs (including benfluorex) have subsequently been withdrawn from the market, several cases of patients requiring valve surgery late after the cessation of therapy have been reported, emphasizing the long-term implications of DIVHD.2,3 Moreover, the exact incidence of patients presenting DIHVD is difficult to establish. The clinical presentation is variable, and some patients were taking multiple anorectic drugs. Reporting of echocardiographically detected DIVHD was highest in the USA when funding became available after several damage claims and has dramatically decreased after reimbursement was suppressed. In the particular case of benfluorex, the number of out of label prescriptions in obese patients without diabetes is not precisely known, making the definition of an appropriate control group even more difficult. Although for benfluorex, the relationship with the development of DHIVD is clearly established, the causality is less well demonstrated than for other drugs.4 The presence of trivial to moderate aortic regurgitation (AR) or moderate-to-severe mitral regurgitation (MR) was the criterion proposed by the FDA to confirm fenfluramine-induced valvulopathy in the late nineties. 5 In younger patients under the age of 50 years with a low background prevalence of AR and MR, such abnormalities can be easily identified. Conversely, in older patients with Parkinson’s disease, pre-existing valvular sclerosis and calcifications are relatively
155
Editorial
References 1. Mare´chaux S, Rusinaru D, Jobic Y, Ederhy S, Donal E, Reant P et al. Food and Drug Administration criteria for the diagnosis of drug-induced valvular heart disease in patients previously exposed to benfluorex: a prospective multicenter study. Eur Heart J Cardiovasc Imaging 2015;16:158 –65. 2. Dahl CF, Allen MR, Urie PM, Hopkins PN. Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals. BMC Med 2008;6:34. 3. Greffe G, Chalabreysse L, Mouly-Bertin C, Lantelme P, Thivolet F, Aulagner G et al. Valvular heart disease associated with fenfluramine detected 7 years after discontinuation of treatment. Ann Thorac Surg 2007;83:1541 –3. 4. Droogmans S, Cosyns B, Van Camp G. Pergolide and valvular heart disease: the lower the better? Eur J Echocardiogr 2008;9:717 –8. 5. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services interim public health recommendations, November 1997. MMWR Morb Mortal Wkly Rep 1997;46:1061 – 6. 6. Cosyns B, Droogmans S, Rosenhek R, Lancellotti P. Drug-induced valvular heart disease. Heart 2013;99:7 –12. 7. Lancellotti P, Tribouilloy C, Hagendorff A, Popescu BA, Edvardsen T, Pierard LA et al. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging. Scientific Document Committee of the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2013;14:611 –44. 8. Drake WM, Stiles CE, Howlett TA, Toogood AA, Bevan JS, Steeds RP et al. A cross-sectional study of the prevalence of cardiac valvular abnormalities in hyperprolactinemic patients treated with ergot-derived dopamine agonists. J Clin Endocrinol Metab 2014;99:90 –6. 9. Weissman NJ, Sanchez M, Koch GG, Smith SR, Shanahan WR, Anderson CM. Echocardiographic assessment of cardiac valvular regurgitation with lorcaserin from analysis of 3 phase 3 clinical trials. Circ Cardiovasc imaging 2013;6:560–7. 10. Lorcaserin. In obesity: unacceptable risks. Prescrire Int 2014;23:117–20.
Downloaded from by guest on November 13, 2015
induced VHD-related endpoints reported in the literature were not included in the preclinical evaluation for lorcaserin (proliferative markers, echocardiography). A recent publication by Weissman and colleagues9 compiling the echocardiographic follow-up of 5249 patients of three-phase, three clinical trials exposed to lorcarserin concluded that the rate of echocardiographic valvulopathy was similar to placebo. In this study, the FDA criteria for DIHVD and the change in regurgitation grade were used for analysis of the data. Following the results of Marechaux et al., this may lead to misinterpretation of the data and false reassurance regarding the use of this drug, as already pointed by others.10 To summarize, regarding drug-induced valve disease, the method used to characterize the type and severity of the valvular lesion that is screened for changes in the sensitivity and specificity of disease detection. Moreover, the objective definition of the epidemiology of DIVHD is dependent on a number of factors: the performance and/or interpretation of the echocardiogram in a non-blinded fashion and other potential co-determinants including pre-existent VHD, age, obesity, diabetes and hypertension. By consequence, great vigilance is still required. On one hand, the late effect of valvulopathic drugs may lead to valve disease even a long time after withdrawn from the market or cessation of these drugs. On the other hand, new drugs released on the market may cause more harm than initially expected.
